1. Field of the Invention
The present invention relates to liposomes, liposomal compositions, and methods suitable for the delivery of active agents.
2. Description of the Related Art
A major challenge facing medical science and the pharmaceutical industry, in particular, is to develop methods for providing therapeutic agents to appropriate tissues or cells at a sufficient dosage to provide a therapeutic benefit, without prohibitively harming the patient being treated. Accordingly, it is an important goal of the pharmaceutical industry to develop drug delivery devices and methods that provide increased efficacy with decreased associated toxicity. A variety of different general approaches have been taken, with various degrees of success. These include, e.g., the use of implantable drug delivery devices, the attachment of targeting moieties to therapeutic compounds, and the encapsulation of therapeutic compounds in carriers, e.g., liposomes, to modulate drug biodistribution and the duration of drug exposure.
Liposomes are particulate carriers and, hence, tend to remain within the blood compartment, as they are not able to extravasate across the continuous endothelial lining present in most blood vessels. At disease sites, however, the blood vessels may be leaky, allowing liposome extravasation and accumulation in the interstitial space. In tumors, for example, the immature neovasculature tends to exhibit pores or defects that can allow liposomes of appropriate size to exit the blood vessels (Yuan et al., Cancer Research 54: 3352-3356, 1994). Similarly, at sites of infection or inflammation, the endothelial permeability barrier can be compromised, allowing liposomes to accumulate in these regions. In contrast, the blood vessels present in most normal, healthy tissues tend to have continuous endothelial linings. Hence, liposomal delivery can reduce drug exposure to these areas. Exceptions are the organs of the mononuclear phagocyte system (MPS), such as the liver and spleen, where fenestrated capillaries are present.
In efforts to develop more effective therapeutic treatments, a variety of compounds have been formulated in liposomes. For example, many anticancer or antineoplastic drugs have been encapsulated in liposomes. These include vinca alkaloids, alkylating agents, nitrosoureas, platinum co-ordination complexes, antimetabolites, anthracyclines, and camptothecins. Studies with liposomes containing anthracycline antineoplastics have clearly shown reduction of cardiotoxicity and prolonged survival of tumor bearing animals compared to controls receiving free drug. In addition, liposomal formulations of antibiotics, anti-inflammatory agents, and antifungal drugs have been described.
In order to achieve efficient drug delivery to disease sites using liposomal carriers, however, the liposomes should exhibit a relatively long plasma circulation half-life to increase the likelihood of extravasate during passage through the site. In addition, drug release from the liposomes should be slow to reduce drug loss prior to carrier accumulation at the disease site. Further, drug activity is often dependent on the duration of drug exposure. In order to optimize efficacy, therefore, slow drug release from the liposomes may be required.
Considerable efforts have been made to identify liposomal carrier compositions that show slow clearance from the blood, and long-circulating carriers have been described in numerous scientific publications and patents. Such long-circulating carriers may employ polymer coatings, e.g., polyethylene glycol (PEG), to reduce uptake by the MPS (reviewed by Allen and Stuart in Liposomes: Rationale Design, Janoff, A. S. (ed), Marcel Dekker Inc., New York (1999); Allen et al., Biochimica et Biophysica Acta 1066: 29-36, 1991) or may employ specific lipid compositions, such as ganglioside (U.S. Pat. No. 4,837,028; Allen and Choon, FEBS Letters, 223: 4246, 1987), or sphingomyelin and cholesterol (U.S. Pat. No. 5,543,152; U.S. Pat. No. 5,741,516; U.S. Pat. No. 5,814,335). Efforts have also been made to control drug leakage or release rates from liposomal carriers, using for example, various lipid components or a transmembrane potential to control release (U.S. Pat. No. 5,077,056). Alternatively, drug release rates may be controlled by precipitation of the drug within the liposomal carriers (U.S. Patent Publication No. 2002/0119990-A1) as indicated by the previous studies, not all lipid formulations are equal for drug delivery purposes and extensive research continues into formulations which demonstrate preferred characteristics for drug loading and storage, drug administration, pharmacokinetics, biodistribution, leakage rates, tumor accumulation, toxicity profile, and the like. Accordingly, while numerous liposomes and lipid-based drug delivery vehicles have been developed, there is clearly still a need in the art for improved liposomal compositions, including liposomes that provide reduced levels of clearance and slow drug release.